Non-pharmacological interventions targeting mobility among people with advanced cancer: a systematic review

Purpose To synthesise evidence evaluating non-pharmacological interventions targeting mobility among people with advanced cancer, considering the type, efficacy and contextual factors that may influence outcome. Methods Systematic review of studies of non-pharmacological interventions in adults (≥ 18 years) with advanced (stage III-IV) cancer, and assessing mobility using clinical or patient-reported outcome measures. Searches were conducted across three electronic databases (MEDLINE, EMBASE and CINAHL) up to June 2024. Methodological quality was assessed using Joanna Briggs Institute tools and contextual factors were evaluated through the Context and Implementation of Complex Interventions framework. A narrative synthesis was conducted due to clinical heterogeneity of included studies. Results 38 studies encompassing 2,464 participants were included. The most frequent mobility outcome measure was the 6-min walk test (26/38 studies). Exercise was the most common intervention, (33 studies: 27 aerobic and resistance, 5 aerobic, 1 resistance versus aerobic training) and improvements in mobility were found in 21/33 outcomes. Electrotherapy interventions led to significant improvements in mobility in 3/5 studies. Geographical factors (e.g. distance, transport, parking requirements) potentially limited participation in 18/38 studies. A lack of ethnic diversity among populations was evident and language proficiency was an inclusion criterion in 12 studies. Conclusion Exercise and neuromuscular electrical stimulation appear to improve mobility outcomes in advanced cancer. The evaluation of other non-pharmacological interventions targeting mobility should consider access and inclusivity, and be adaptable to the needs of this population. Supplementary Information The online version contains supplementary material available at 10.1007/s00520-024-08767-x.


Introduction
Cancer is one of the leading causes of global morbidity and mortality worldwide [1].The burden posed by advanced cancer, i.e. progressive and incurable with extensive local or metastatic involvement [2], reduces functional capacity and mobility status [2,3].People with advanced cancer often report debilitating symptoms, physical limitations, and reduced quality of life, culminating in difficulty completing activities of daily living [4] and emotional distress for both the individual and their family [5].
Mobility status, defined as "an individual's ability to move oneself (either independently or by using assistive devices or transportation) within environments that expand from one's home to the neighbourhood and to regions beyond" [6], is an important but often overlooked concept [3,7].Declining mobility status is considered to be one of the most unpleasant symptoms that reduces quality of life in people with advanced cancer [3,7].Consistent negative correlations are found between the loss of mobility and worsening pain, fatigue and/or breathlessness [8], and on psychosocial well-being [9].
Individuals with advanced cancer may become deconditioned and find themselves entrapped in a vicious cycle, whereby pain, fatigue, and breathlessness restrict their mobility, consequently exacerbating these symptoms further [5].The importance of taking proactive steps to address mobility issues throughout the cancer journey is clear.There is increasing recognition of the role of non-pharmacological interventions in comprehensive cancer management [10].In cancer rehabilitation these interventions encompass exercise programmes, breathlessness and fatigue self-management, mindfulness-based techniques, nutritional counselling, psychosocial support and more [10,11].Despite evidence of benefit, staff and space constraints may slow their implementation into routine cancer care [12].
Regarding interventions that may impact on mobility in advanced cancer, previous reviews have extensively evaluated the role of exercise [8,9,13,14].These reviews conclude that exercise is safe and associated with improved physical functioning and quality of life.No review to date has evaluated the range of non-pharmacological interventions available for people with advanced cancer, focusing on mobility as a primary outcome of interest.Moreover, a consideration of the level of resources, or the contextual factors that may affect mobility interventions, such as geographical or personal factors is required.Therefore, we aimed to provide a comprehensive synthesis of evidence for nonpharmacological interventions targeting mobility in people with advanced cancer.Our objectives were to: (i) identify and evaluate the efficacy of non-pharmacological interventions in optimising mobility; (ii) evaluate the staffing time, types of settings, equipment and other resources required to deliver the interventions; and (iii) explore contextual factors that may impact on the generalisability of interventions. Methods.
We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [15].The protocol was registered on PROSPERO (ID: CRD42023425824).

Inclusion and exclusion criteria
Studies of any design that evaluated non-pharmacological interventions in adults (≥ 18 years) with confirmed advanced cancer and assessed mobility using clinical or patient-reported outcome measures (PROM) were included.Non-randomised studies of interventions (NRSIs) were included to ensure a comprehensive understanding of the evidence.NRSIs offer valuable insights, balancing the rigor of randomised controlled trials (RCTs) with the contextual richness of observational studies, thereby supporting decision-making in both policy and practice [16].Advanced cancer was defined as stages III-IV for solid tumours.For haematological cancers, due to staging difficulties, we adopted the operational definition proposed by Cheville et al., [17], wherein lymphoma was considered stage III, and myeloma and myelofibrosis syndrome were categorised as stage IV, regardless of their distribution, as these are considered systemic conditions.Moreover, we only included studies where the participant sample comprised ≥ 95% individuals with advanced cancer.This selection criterion was adopted to mitigate some clinical heterogeneity across the included studies.We excluded incomplete or unpublished studies, case reports, conference proceedings and papers not in English.

Search strategy
A comprehensive search of electronic databases, including MEDLINE and EMBASE (via Ovid) and CINAHL (via EBSCO) was conducted (Full search strategy: Supplementary file Tables S1-3).Using Medical Subject Headings (MeSH), truncation, and Boolean operations, the search covered the inception of each database until June 2024.Reference lists of eligible articles, previous systematic reviews, and relevant guidelines were also hand-searched for additional citations.

Selection of studies
An online systematic review manager, Rayyan, was used to handle records and remove duplicates.Eligibility criteria were initially applied to titles and abstracts and reviewed by one of three authors (CP, JB and MM).Full-text articles were retrieved from titles and abstracts of articles that met the review criteria or lacked sufficient information to determine suitability.The retrieved articles were then imported into Zotero, a reference management software, for full-text screening by CP and one or more authors (SA, MB, SC, LN, ET, EV).Disagreements in screening were resolved through discussion between CP, JB and MM.

Data extraction and analysis
A standardised data extraction form was used to collect information on study design, methodology, intervention specifics, setting details, sample characteristics, contextual factors, mobility outcomes, and results.Data extraction was performed by CP and checked for accuracy by at least one other author (SA, MB, SC, LN, ET, EV).For our analysis, we utilised the mean scores, standard deviations, and other statistical data as provided by the original study authors.We tabulated the p-values, confidence intervals and effect sizes (Cohen's d and Glass's delta) as reported in the studies.

Methodological quality assessment
The methodological quality of included studies was independently assessed by CP and one or more authors (SA, MB, SC, LN, ET, EV).RCTs were assessed using the Joanna Briggs Institute (JBI) RCT appraisal tool [18].The remaining study designs were assessed with the JBI Quasi-Experimental tool [19].The tools were not used to exclude papers but to understand the overall strengths and weaknesses of included literature.

Contextual factors
Contextual factors were evaluated using the Context and Implementation of Complex Interventions (CICI) framework [20], offering a structured approach to complex interventions through three dimensions of context, implementation, and setting [20].For the purposes of this review, the following contextual domains were considered: geographical, epidemiological, socio-cultural and socioeconomic.Each study was reviewed by CP and one or more authors (SA, MB, SC, LN, ET, EV), with potential contextual factors identified through discussion and understood as general themes across studies.

Study retrieval and analysis
The initial search yielded 16,831 articles and following the screening of titles and abstracts, 201 full-text articles were retrieved for further evaluation (Fig. 1).Subsequently, 38 articles met the eligibility criteria and were included in the review [17,.The main reason for exclusion of fulltext articles was < 95% of the study sample having advanced cancer (n = 145).Given the significant heterogeneity among the included studies, a meta-analysis was deemed unsuitable.Instead, a narrative synthesis was employed with data presented as tabulated summaries.Data from each article were analysed through vote counting, focusing on the statistical significance of the outcomes.Vote counting was selected due to the heterogeneity between studies and served as a pragmatic approach for conducting an exploratory analysis and to offer preliminary insights [58].

Methodological quality assessment
Across included studies, RCTs generally demonstrated good internal validity through the application of true randomisation, baseline participant similarity, and appropriate statistical analyses (Full quality assessments: Supplementary file Tables S4-5).A notable limitation was the absence of blinding for both participants and treatment providers, although this was anticipated given the inherent characteristics of the interventions.In a few cases, baseline similarity of treatment groups was unclear and there was insufficient clarity regarding the methods used to measure outcomes.In quasi-experimental studies, the hypothesised cause-andeffect relationships were easily identifiable.However, it also often remained unclear whether outcomes were measured with sufficient reliability.

Resistance exercise
One study [35] investigated a resistance training programme as a standalone intervention.They conducted a 10-week randomised comparative study evaluating an aerobic programme versus a resistance training programme.They found that both resistance (baseline: 9.38 ± 2.10 points; post-intervention 9.91 ± 1.95 points) and cardiovascular (baseline: 9.77 ± 2.25 points; post-intervention: 10.45 ± 2.05 points) training resulted in statistically significant improvements in the Short Physical Performance Battery, without substantial differentiation between the exercise types [35].

Aerobic exercise
Six studies evaluated an aerobic based intervention [23,28,29,35,49,50], with two studies finding a significant change in mobility following aerobic training [28,35].Three studies evaluated walking programmes [23,28,50], one evaluated treadmill training [49], one evaluated an aerobic programme alongside nutritional and behaviour change advice [29], and one evaluated an aerobic programme versus a resistance programme [35].The intensity and frequency of training varied between studies.For example, in two walking programme studies [23,28] specific step-count goals were utilised, with one study aiming for a weekly increase of 400 daily steps over 12 weeks [23], whilst the other aimed for a weekly increase of 1000 daily steps over six-months [28].Participants who already achieved ≥ 10,000 steps per day were encouraged to maintain their activity levels.The programme with the longer duration and higher step-count goal demonstrated statistically significant improvements in 6MWT (baseline 451.6 ± 99.7; post-intervention 482.6 ± 106.3; p < 0.001) [28].The other walking programme required participants to walk for 150 min per week over 12 weeks, but found no significant improvement in mobility [50].Another study conducted a twice-weekly centre-based intervention and found a positive impact on clinical measures of mobility as described earlier [35].An eight-week multicomponent aerobic based programme and a treadmill based intervention over 12 weeks found no statistically significant improvement in mobility outcomes [29,49].[39,52], counselling [39], referrals to physiotherapy [17], electrotherapy [42] and breathing exercises combined with manual chest physiotherapy techniques [42,46].Six of these studies were home-based [17,25,30,32,43,55].Two of these studies reported a significant improvement in 6MWT in the intervention group following a 12 week intervention in one study (baseline: 384.2 ± 74.6 m; postintervention: 447.4 ± 50.4 m; p < 0.001) [43] and an eightweek intervention in the other (baseline: 531.4 ± 136.2 m; post-intervention mean change: 40 ± 23 m) [55].Two studies reported statistically significant improvements in AM-PAC mobility scores in the intervention groups [17,25].One of these studies, evaluated a home-based combined exercise programme over eight-weeks (mean difference 4.88 ± 4.66 points; p = 0.002) [25], whilst the other evaluated a six-month telerehabilitation intervention comprising of a combined home-based exercise programme and outpatient physiotherapy referral (baseline 60.2 ± 3.7 points; post-intervention between group difference 1.3 points; p = 0.03) [17].

Electrotherapy
Five studies evaluated the efficacy of electrotherapy [36,37,40,47,48], with three studies finding significant improvements in mobility outcomes [40,47,48].Electrotherapy protocols varied greatly in terms of stimulation site, frequency (Hz), session number and overall duration.In two studies, dietary advice was combined with whole-body electrical muscle stimulation (WB-EMS) during active range of motion activities and applied to major muscle groups [47,48].The remaining three studies evaluated neuromuscular electrical stimulation (NMES) as a single component intervention [36,37,40].One study utilised transcutaneous electrical nerve stimulation in conjunction with exercise [42], but used this modality for pain relief rather than functional gains and was consequently categorised as a multi-component exercise intervention rather than an electrotherapy-based intervention.
Two studies [36,37] encouraged daily NMES usage within their studies, targeting the quadriceps but found no improvements in mobility outcomes.One study [40] recommended a progressive increase use of NMES over the four week study targeting the quadriceps and hamstrings with a combination of low and high frequency stimulation.The study found statistically significant improvements in 6MWT (baseline: 232 ± 69 m; post-intervention: 309 ± 61 m; p = 0.040) but no statistically significant improvement in TUG [40].Two studies [47,48] recommended at least two days rest between WB-EMS training to allow for muscle recovery and opted for twice weekly training sessions, with participants wearing a vest, hip belt, upper arm, and thigh cuffs with integrated electrodes.Both studies found statistically significant improvements in the interventions group's 6MWT scores (baseline: 521.6 ± 104.5 m; post-intervention 577.1 ± 95.4 m; p = 0.036 [47]; baseline 543.8 ± 99.5 m; post-intervention coefficient 44.57m; 95% CI 13.83 to 75.30; p = 0.006 [48]).

Contextual factors
Geographical contextual factors were identified as potential barriers to participation in 18 studies [24-27, 31, 33, 35, 36, 38, 39, 41, 44, 45, 47, 48, 51, 52, 56].Participants reportedly faced transportation and parking challenges when traveling to healthcare facilities for the intervention, as highlighted in one study [24].Two studies determined participants' eligibility based on the participant's reported ability to attend the intervention sessions twice weekly, leading to those living too far away from the study centre to be allocated to the control group or excluded from the study [47,48].

Main findings
This review aimed to provide a comprehensive synthesis of non-pharmacological interventions that evaluated mobility in people with advanced cancer.The review included 38 randomised and non-randomised studies with 2464 participants overall.Our main findings were: i) both exercise and neuromuscular electrical stimulation interventions had an overall positive impact on mobility outcomes; ii) we identified a disparity between clinical and patient-reported measures in detecting changes in mobility status.Observed improvements in clinical measurement tools assessing mobility status were not always reflected in patient-reported outcomes when measured in parallel; iii) regarding resources and context, the centre-based nature of many interventions as well as a requirement for native language proficiency, may have limited access to, and inclusivity of, interventions for this group.

Interventions
Our findings suggest exercise and neuromuscular electrical stimulation interventions may help optimise mobility among people with advanced cancer.However, the heterogeneity across studies precluded meta-analysis, so the narrative synthesis findings should be interpreted with due caution.
Exercise-based studies typically focused on the physical domain of mobility, targeting areas such as muscle strength, endurance, and flexibility.Theoretically, interventions targeting symptoms such as breathlessness, fatigue, pain, nutrition and psychosocial domains may indirectly impact on mobility [59,60].For example, holistic breathlessness services aim to reduce breathlessness, which may positively influence the psychosocial mechanisms described within Webber and colleagues' model of mobility [6], such as confidence and self-efficacy [61].Additionally, occupational therapy interventions, such as home modifications and provision of assistive devices align with the psychosocial and environmental domains of Webber and colleagues' model [6], and may influence factors such as falls risk, promote energy conservation, and influence an individual's capacity and willingness to mobilise [62].Notably, these types of single component interventions were excluded as many did not use mobility measures [63][64][65] or sub-analysis of mobility outcomes were not reported within study results [66].Future studies that directly or indirectly target mobility, should incorporate outcome measures that capture changes across the multiple domains of mobility.

Measurement
Studies in our review employed a combination of clinical tools and PROM.Clinical measures, such as the 6MWT, evaluate the impact of interventions on exercise capacity and serve as good predictors of community mobility [67], but solely measure the physical domain of mobility.PROM such as the EORTC-QLQ-C30 and SF-36 focus on healthrelated quality of life, but both assess different domains of mobility.We had anticipated that improvements in clinical measures, like the 6MWT, would equate to enhanced physical function in the PROM [68].However, our review reveals that improvements in the clinical measures of mobility were not always reflected in PROM.This discrepancy may be attributed to limited statistical analysis and reliance on vote counting.Alternatively, the discrepancy may be linked to most studies evaluating interventions targeting the physical domain of mobility, whereas the PROM, even though assessing physical function, include various interconnected mobility domains [69], such as psychosocial and environmental factors [6].As a result, improvements in the specific physical clinical measures might not be reflected in the broader aspects of mobility assessed within the PROM.
Moreover, PROM such as the EORTC-QLQ-C30 and SF-36 may not capture the nuances of mobility in a natural setting [70].These instruments focus on assessing mobility domains situated within the "Activities and Participation" component of the International Classification of Functioning, Disability, and Health (ICF) framework [70,71].However, within this ICF component, these PROMs offer limited evaluation of mobility concerning community and social participation, domestic life, and the ability to mobilise in different settings [70].Psychological, emotional and social factors contribute to an individual's walking experience [72], but current measurement approaches, which particularly rely on clinical measures, may not fully capture the diverse dimensions of mobility.Only a few studies in our review evaluated mobility in natural settings, where individuals navigate domestic life, engage in community activities and experience the broader facets of mobility.Tools such as the PROMIS Cancer Item Bank for Physical Function, AM-PAC, World Health Organisation Disability Assessment Schedule (WHODAS), and PASE, may offer a more comprehensive assessment of mobility in people with advanced cancer [70].

Access and inclusivity
The geographical considerations highlighted in this review emphasise challenges associated with centre-based interventions, including distance from the site, transportation, and parking.A majority of studies were conducted in large metropolitan areas, potentially limiting the generalisability of findings to rural or remote populations [73].Exploring alternative delivery methods, particularly for those benefiting from non-pharmacological interventions but facing access challenges, is crucial.The effectiveness of tele-rehabilitation, catalysed further by the recent COVID-19 pandemic, underscores the potential for alternative healthcare modalities [17].A third of the reviewed studies investigated home or community-based interventions, incorporating telephone and/or online support, with 45% showing significant improvements in mobility.Whilst telerehabilitation in advanced cancer has shown to be cost-effective [74], further research is needed to compare outcomes across various delivery models and assess their impact on factors such as quality of life [75].
Regarding inclusivity, the seven studies that reported ethnicity revealed a significant overrepresentation of white participants (≥ 80%).While this may be representative of the local population, programmes should actively eliminate barriers to inclusivity, ensuring equitable representation for traditionally underserved and underrepresented populations in both research and healthcare [76].

Considerations for future research
While exercise and electrotherapy interventions suggest positive impacts on mobility, there is a significant gap in addressing the broader concept of mobility beyond physical functioning.Future studies should integrate the various domains in Webber and colleagues' model [6], acknowledging their interconnected nature and influence on mobility, whilst also considering geographical, sociocultural and socioeconomic factors that may impact on access and inclusion.Integrating secondary measures like PROM that assess mobility within a natural setting, will offer a comprehensive understanding of these interconnected domains.Moreover, the absence of single component interventions, such as holistic breathlessness services and occupational therapy, underscores the need to explore these areas to understand their potential impact on mobility.

Strengths and limitations
This review adheres to the recommendations outlined in the PRISMA statement [15].Transparency in reporting was upheld through the development of a comprehensive study protocol, and to minimise judgment errors and bias, screening and data extraction were conducted independently by two or more authors.Some limitations also warrant consideration.Firstly, due to the level of heterogeneity of the included studies, a metanalysis was not suitable.The selected method of vote counting, grounded in statistical significance, offers limited insights into the magnitude of effects and does not consider variations in the relative sizes of individual studies [77].Additionally, studies characterised by inadequate statistical power, which do not sufficiently exclude clinically significant effects, risk being counted as not demonstrating a therapeutic benefit [77].Secondly, the inclusion criteria, requiring studies to have ≥ 95% of their sample composed of individuals with advanced cancer, led to the exclusion of studies that nearly met this threshold, and may have resulted in the omission of valuable data.Lastly, due to a lack of resources, a risk of selection bias exists, as only studies published in English were included.

Conclusion
This systematic review suggests a positive impact of both exercise and neuromuscular electrical stimulation interventions on mobility outcomes.However, included studies were mostly conducted in high resource countries and may not be generalisable to other settings.Opportunities for future research include the use of mobility outcomes to evaluate the impact of tailored interventions targeting different domains of mobility.Population and contextual factors should be carefully considered to promote inclusivity and to eliminate barriers for diverse populations.

Table 1
Characteristics of included studies for narrative review [17]r = not reported AM-PAC CAT Ambulatory Post Acute Care Computer Adaptive Test, ECOG Eastern Cooperative Oncology Group, KPS Karnofsky Performance Score, NSCLC Non-small cell lung cancer, SCLC Small cell lung cancer, SD Standard deviation, WHO World Health Organisation a SD not specified for total study participants.bBaselineperformancestatus not reported.Values presented represent participants' eligibility criteria for the study.cChevilleetal.,[17]hadthree trial arms.As trial arm 3 included a pharmacological element, this was excluded.Data presented pertains to arms 1 and 2 only.

Table 2
Intervention details, measure of mobility and results